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A novel t(11;14)(q13;q32) translocation involving Pellino3 links innate immune and inflammatory signaling to a myeloproliferative neoplasm

2016-10-15 21:07:57

International Journal of Clinical and Experimental Pathology; 15 October 2016: /ISSN:1936-2625/IJCEP0033883

Hua Guo, Nayyara Mahmood, Judith Brody, Dipti Gheewala, Craig Devoe, Steven L Allen, Silvat Sheikh-Fayyaz, Chandrika Sreekantaiah, Gokul Kandala, Xinmin Zhang



Abstract


Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) plays a central role in innate immune response and
inflammation. Pellino3 is an E3 ubiquitin ligase which has important regulatory functions in TLR signaling. We identified a novel t(11;14)(q13;q32) translocation in a patient with JAK2 positive myeloproliferative neoplasm who later developed acute myeloid leukemia. FISH analysis revealed no CCND1-IGH fusion. By sequential FISH using a series of bacterial artificial clone (BAC) probes, we demonstrated that the translocation involved Pellino3, resulting in its translocation to der(14) and overexpression of Pellino3 protein. This is the first report linking the Pellino3 signaling to myeloproliferative neoplasm.



Introduction


Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) plays an important role in innate immune response and inflammation. The engagement of TLR/IL-1R recruits the adaptor protein MYD88 or TRIF, which initiates a cascade of
downstream events, ultimately resulting in NFKB activation and the induction of proinflammatory cytokines. The ubiquitin proteasome system plays a central role in the regulation of the TLR/IL-1R pathway by controlling levels and activities of signaling molecules. Pellino is a ring class of E3 ubiquitin ligase and has three human family members: Pellino1, Pellino2 and Pellino3.



Pellino3 has diverse functions in the TLR/IL-1R pathway: (1) It catalyzes K63 polyubiquitination of TLR/IL-1R signaling molecules such as IL-1Rassociated kinase 1 (IRAK1) and TNF receptorassociated factor 6 (TRAF6). (2) It is a negative regulator for TLR3 and TLR4 induced interferon ? (IFN?) expression and tumor necrosis factor (TNF) induced apoptosis. (3) It is a mediator of the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) signaling pathway that is important in the homeostatic control of intestinal inflammation. Overexpression of Pellino3 triggers activation of ERK, JNK and P38 MAPK pathways. Pellino3 is required for P38 mediated activation of
cAMP-responsive element-binding protein (CREB). Overexpression of CREB in myeloid cells in transgenic mice induced a myeloproliferative process mimicking human myeloproliferative neoplasm (MPN). Accumulating evidence suggests that Pellino3 may play a role in the pathogenesis of MPN.



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Key Words

Pellino3 | myeloproliferative neoplasm | ubiquitin ligase | TLR/IL-R | JAK2